Oral formulations of certain pharmaceutically active agents are subject to degradation and inadequate absorption following administration to mammals. Attempts have been made to improve the stability and bioavailability of orally administered active agents. For example, liposomes and micelles have been used as drug carriers. See, e.g. U.S. Pat. No. 5,552,156 to Burke; U.S. Pat. No. 4,837,028 to Allen. U.S. Pat. No. 4,849,227 to Cho discloses compositions for oral administration comprising particles consisting of an emulsifying agent and a surfactant wherein an active agent is bound to the surface of the particles, and the particles are coated with a lipid coating. U.S. Pat. No. 5,665,700 to Cho et al. discloses a formulation comprising a hydrophilic phase containing a biologically active material wherein the hydrophilic phase is dispersed in a lipophilic phase to form an emulsion. U.S. Pat. No. 5,858,398 to Cho discloses formulations comprising a microparticle of active agent, phospholipid and surfactant wherein the microparticle is suspended in a micelle.
U.S. Pat. No. 4,615,885 to Nakagame et al. discloses a liposome preparation comprising urokinase and higher fatty acids, a polyalkylene glycol and calcium. Nakagame et al. disclose that the higher fatty acids are incorporated into the membrane of liposome at a concentration such that the phospholipid remains in lamella structure. The concentration of fatty acids in the membrane is preferably 5-15% by weight. Higher concentrations result in formation of micelles having the fatty acid at the center, and according to Nakagame et al. will thereby lower or eliminate the ability of the composition to carry the drug.
Micelles are known as drug delivery systems, but generally suffer from poor stability, resulting in separation of the active agent from the micelle. Attempts to promote the absorption of insulin and other macromolecules from the intestine by applying surfactants, triglycerides and lipid-surfactant mixed micelles have generally met with poor results. Muranishi et al. (1978) J. Pharm. Dyn. 1:28; Inouye et al. (1979) J. Pharm. Dyn. 2:286; Danforth et al. (1980) J. Pharm. Dyn. 4:219; Crane et al. (1968) Diabetes 17:625.
U.S. Pat. No. 5,858,398 disclose stabilization of micelles by addition of hydrophilic cholesterol and phospholipids in vitro.
In accordance with the present invention, it has been discovered that encapsulation of a pharmaceutically active agent with a layer of C12-C18 fatty acids forms a pro-micelle which, upon administration to a mammal, provides a stable micelle. The pro-micelle effectively delivers the pharmaceutically active agent, and does not require stabilization in vitro with cholesterol and phospholipid.